What are the first-line treatment options for managing hypertension?

First-Line Antihypertensive Medications

The four first-line medication classes for hypertension are thiazide or thiazide-like diuretics, ACE inhibitors, angiotensin receptor blockers (ARBs), and calcium channel blockers—all have equivalent efficacy in reducing cardiovascular morbidity and mortality. 1

Initial Treatment Strategy

For most patients with confirmed hypertension (BP ≥130/80 mmHg), upfront low-dose combination therapy with two drugs from different classes is now recommended as the preferred initial approach. 1 This strategy achieves faster blood pressure control, improves adherence, and reduces side effects compared to sequential monotherapy titration. 1

When to Start with Monotherapy vs. Combination Therapy

• Start with single-drug therapy if BP is 130-139/80-89 mmHg and the patient has low cardiovascular risk or elevated BP without hypertension diagnosis. 1, 2
• Start with two-drug combination if BP is ≥140/90 mmHg or if BP is 130-139/80-89 mmHg with high cardiovascular risk (diabetes, chronic kidney disease, established CVD, or ≥10% 10-year ASCVD risk). 1, 2
• Start with two drugs immediately if BP is ≥160/100 mmHg, as this represents stage 2 hypertension requiring prompt control. 1, 2

The Four First-Line Drug Classes

1. Thiazide or Thiazide-Like Diuretics

• Chlorthalidone and indapamide are preferred over hydrochlorothiazide because they have longer duration of action and superior cardiovascular event reduction in clinical trials. 1
• Particularly effective in Black patients as monotherapy. 1, 2
• Chlorthalidone was superior to amlodipine and lisinopril in preventing heart failure in the ALLHAT trial. 1

2. ACE Inhibitors

• Mandatory first-line choice in patients with albuminuria (urine albumin-to-creatinine ratio ≥30 mg/g), as they reduce proteinuria and slow progression of kidney disease beyond blood pressure lowering alone. 1, 2
• Strongly recommended for patients with coronary artery disease, heart failure, or post-myocardial infarction. 1, 3
• Less effective than calcium channel blockers or diuretics in Black patients for stroke prevention. 1, 2
• Absolute contraindication in pregnancy and fertile women not using reliable contraception—must be avoided or immediately discontinued if pregnancy occurs. 4

3. Angiotensin Receptor Blockers (ARBs)

• Equivalent efficacy to ACE inhibitors for cardiovascular outcomes and blood pressure reduction. 5
• Same indications as ACE inhibitors: albuminuria, coronary artery disease, heart failure, diabetes with nephropathy. 1, 2, 6
• Better tolerated than ACE inhibitors with significantly lower rates of cough and angioedema. 5
• Never combine ACE inhibitors with ARBs—this increases adverse effects (hyperkalemia, acute kidney injury) without additional benefit. 1, 2
• Absolute contraindication in pregnancy and fertile women not using reliable contraception. 4

4. Calcium Channel Blockers

• Dihydropyridine CCBs (amlodipine, nifedipine extended-release) are preferred for initial hypertension therapy. 4, 2
• First-line choice for Black patients as monotherapy, more effective than ACE inhibitors or ARBs in this population. 1, 2
• Preferred first-line option for fertile women with diabetes or hypertension because they are safe and effective in pregnancy, unlike ACE inhibitors/ARBs. 4
• Equivalent to diuretics for reducing all cardiovascular events except heart failure. 1

Preferred Combination Strategies

The most effective two-drug combinations are: 1

• ACE inhibitor or ARB + calcium channel blocker
• ACE inhibitor or ARB + thiazide-like diuretic
• Calcium channel blocker + thiazide-like diuretic

Single-pill combinations are strongly preferred over separate pills because they improve adherence and persistence. 1

Special Population Considerations

Diabetes with Hypertension

• ACE inhibitor or ARB is mandatory first-line if albuminuria is present (urine albumin-to-creatinine ratio ≥30 mg/g). 1, 2
• Target BP <130/80 mmHg. 1, 2
• If no albuminuria, any of the four first-line classes are appropriate. 1

Chronic Kidney Disease

• ACE inhibitor or ARB is first-line because they slow CKD progression and reduce albuminuria. 2
• Continue ACE inhibitor/ARB even as eGFR declines to <30 mL/min/1.73 m² for cardiovascular benefit. 1

Black Patients

• Calcium channel blocker or thiazide diuretic as monotherapy is more effective than ACE inhibitor or ARB. 1, 2
• ACE inhibitors are 36% less effective than CCBs and 30% less effective than diuretics for stroke prevention in Black patients. 1

Fertile Women

• Calcium channel blocker is the preferred first-line choice because ACE inhibitors and ARBs cause fetal damage and are absolutely contraindicated. 4
• Alternative options include methyldopa or labetalol, both safe in pregnancy. 4

Elderly Patients (≥65 years)

• Target SBP <130 mmHg if tolerated, though <140/80 mmHg is acceptable based on frailty. 2
• Start with lower doses and titrate gradually to avoid orthostatic hypotension. 1
• Any of the four first-line classes are effective. 1

Blood Pressure Targets

• <130/80 mmHg for most adults <65 years with hypertension. 2
• <130/80 mmHg for patients with diabetes, CKD, or established CVD regardless of age. 1, 2
• SBP <130 mmHg for adults ≥65 years, with <140/80 mmHg acceptable in frail elderly. 2

Critical Monitoring Requirements

• Monitor serum creatinine and potassium within 7-14 days after initiating ACE inhibitors, ARBs, or mineralocorticoid receptor antagonists. 2
• Measure blood pressure in both seated and standing positions in elderly patients to detect orthostatic hypotension. 1
• Follow-up 2-4 weeks after medication initiation or dose changes, with goal of achieving target BP within 3 months. 2

Resistant Hypertension (Uncontrolled on Three Drugs)

Resistant hypertension is defined as BP ≥140/90 mmHg despite appropriate lifestyle modifications plus three antihypertensive drugs (including a diuretic) at maximally tolerated doses. 1

• Add spironolactone (mineralocorticoid receptor antagonist) as the fourth-line agent—it is more effective than beta-blockers for resistant hypertension. 1
• If spironolactone is not tolerated, consider eplerenone (50-200 mg daily, possibly twice daily) or a vasodilating beta-blocker (labetalol, carvedilol, nebivolol). 1
• Refer to hypertension specialist for evaluation of secondary causes and adherence assessment. 1

Common Pitfalls to Avoid

• Never combine ACE inhibitor with ARB—this increases harm without benefit. 1, 2
• Do not use ACE inhibitors or ARBs in fertile women without reliable contraception or pregnancy planning. 4
• Do not use beta-blockers as first-line monotherapy for uncomplicated hypertension—they are less effective than other classes for stroke prevention and should be reserved for compelling indications (post-MI, heart failure, angina). 1
• Avoid hydrochlorothiazide when chlorthalidone or indapamide are available—the latter have superior cardiovascular outcomes data. 1
• Do not delay treatment in high-risk patients—those with BP ≥160/100 mmHg or BP 130-139/80-89 mmHg with diabetes, CKD, or CVD should start medication immediately. 1, 2